AGGIORNAMENTO STUDI CLINICI IN CORSO

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1 AGGIORNAMENTO STUDI CLINICI IN CORSO
RIUNIONE MITO UDINE 21/06/2018 AGGIORNAMENTO STUDI CLINICI IN CORSO Sandro Pignata

2 OVAIO PRIMA LINEA DI TRATTAMENTO
- PAOLA 1 Chiuso (INT-Napoli) EWOC TRIAL (INT-Milano) Sospeso PRIMA TRIAL (INT-Milano): Ongoing Trust trial (INT, Napoli): Ongoing MITO 28 Pembrolizumab (INT Napoli), MITO 25 Rucaparib (INT Milano), ENGOT OV 39 Atezo-Beva (INT Napoli),

3 PAOLA -1 Study design

4 Date ARCAGY - GINECO 2015

5 Date ARCAGY - GINECO 2015

6 4/15/2019

7 Elderly Women Ovarian Cancer
EWOC Elderly Women Ovarian Cancer Multicenter, randomized trial of carboplatin +/- paclitaxel in vulnerable elderly patients with stage III-IV advanced ovarian cancer  Participating Groups GINECO, AGO, MITO, ANZGOG, Canada, JGOG, GOTIC, NSGO

8 Arm A : carboplatin AUC 5 + paclitaxel 175mg/m² q21 X 6 cycles
Arm B : carboplatin AUC 5-6 q21 X 6 cycles Arm C : carboplatin AUC 2 + paclitaxel 60 mg/m² weekly q28 (d1, d8, d15) x 6 cycles Patient >70 years old GVS* > 3 Rando EWOC DESIGN of Chemotherapy in Advanced OC (stage III-IV - Elderly Vulnerable Pts in an adjuvant or neoadjuvant setting ) *GVS = Geriatric Vunerability Score : - score ADL < 6 - score IADL < 25 - score HADS > 14 - albuminemia < 35g/L - Lymphopenia < 1G/L GVS =  factors with vulnerable score

9 – UPDATE

10 IMPORTANT UPDATED EWOC-1 STUDY
First interim analysis 30 November 2015 : The IDMC concluded that there was no need to close the trial or stop one of the treatment arms but asked to review the safety data when 30 patients will be included in each arm and had received at least 6 cycles of treatment or stopped their treatment prematurely. In response to this IDMC request, the tolerance and efficacy results of the first 92 patients in the trial were submitted to the IDMC on Taking into account that, the data presented did not correspond to planned analysis in the protocol and the risk of concluding on immature data, the Independent Committee recommended to suspend the randomizations and reassess the data on efficacy and tolerance after the first 120 patients have received at least 6 cycles of treatment or prematurely discontinued their treatment. Given the opinion of the Independent Committee, the EWOC-1 Trial Management Group requests the suspension of the RANDOMIZATIONS in the EWOC-1 trial from today until further notice. However, the REGISTRY remains open and we hope that you will continue to include all vulnerable and non-vulnerable elderly patients in the registry. This registry is indeed a tremendous opportunity to validate prospectively the geriatric vulnerability score defined in the EWOC-1 trial.

11 ITALIAN SITES ( 21 pts included; 9 randomized)
Principal Investigator Upadate IRCCS Istituto Nazionale Tumori – Milano Francesco Raspagliesi/ Domenica Lorusso Activated, 11 patients Istituto Nazionale Tumori Pascale - Napoli Sandro Pignata Waiting contract Policlinico Universitario A. Gemelli - Roma Giovanni Scambia Suspended IRCCS Arcispedale Santa Maria Nuova – Reggio Emilia Alessandra Bologna Refusal by the ethics committee CRO IRCCS - Aviano Roberto Sorio Activated, 1 patients AOU Federico II Sabino De Placido IRE-Istituto Nazionale Tumori REGINA ELENA - Roma Patrizia Vici Fondazione del Piemonte per l'Oncologia - Istituto di Candiolo Giorgio Valabrega Activated U.O.Oncologia Medica - Ospedale Vito Fazzi - Lecce Graziana Ronzino ULLS 13, Mirano - Venezia Grazia Artioli Activated, 5 patients Casa Sollievo della Sofferenza - S.Giovanni Rotondo Francesco Petruzzelli Fondazione IRCCS Policlinico S.Matteo di Pavia Stefano Bogliolo Ospedale SS.Trinità - Sora Teresa Gamucci No updates AULSS 21 LEGNAGO Filippo Greco Activated, 2 patients Ospedale di Sassuolo Giovanni Partesotti

12 PRIMA Trial Design 450 pts

13 ENROLLEMENT CLOSED ON FEBRUARY 2018
PRIMA Enrollment    UK 21    CHE 8    SWEDEN 2    Spain 95    Norway 1     Italy 35    Israel 17    Ireland 3    Germany 24    France 31   Finland 11    Denmark    Belgium 40    USA 246    Canada 87    Ukraine 29    Russia 30    Poland 10    Hungary 7    Czech Rep. 12 733 ENROLLEMENT CLOSED ON FEBRUARY 2018

14 CENTRI MITO-MANGO

15 TRUST An open randomized prospective multicenter‐trial
TRIAL ON RADICAL UPFRONT SURGERY IN ADVANCED OVARIAN CANCER TRUST Protocol ID: AGO‐OVAR OP.7 An open randomized prospective multicenter‐trial A project of the AGO Study Group

16 TRIAL ON RADICAL UPFRONT SURGERY IN ADVANCED OVARIAN CANCER
TRUST Primary objective To assess the efficacy of primary‐ compared to interval debulking surgery in patients with advanced ovarian cancer (AOC) with respect to overall survival. Secondary objective To evaluate the safety of complete tumor resection at primary‐ compared to interval debulking surgery and the effect of primary‐ or interval debulking surgery on progression‐free survival (PFS) and quality of life (QoL) as well as surgical morbidity.

17 TRIAL ON RADICAL UPFRONT SURGERY IN ADVANCED OVARIAN CANCER
TRUST Key inclusion criteria Newly diagnosed FIGO stage IIIB‐IV* invasive epithelial ovarian cancer Performance status (ECOG) 0 – 1 ASA score 1 – 2 Assessment of an experienced surgeon, that based on all available information, the patient can tolerate the procedures necessary to achieve a complete tumor resection. * IV only if potentially resectable metastasis Key exclusion criteria Non epithelial ovarian malignancies and borderline tumors. Secondary invasive neoplasms in the last 5 years Recurrent ovarian cancer. Prior abdominal/pelvic radiotherapy. Dementia or significantly altered mental status that would prohibit the understanding and giving of informed consent. Any reasons interfering with regular follow‐up.

18 Randomized till date: 404/686
TRIAL ON RADICAL UPFRONT SURGERY IN ADVANCED OVARIAN CANCER TRUST Primary debulking surgery 6 cycles postoperative chemotherapy Pre-operative in-/exlusion criteria met 1:1 randomization 3 cycles neoadjuvant chemotherapy Interval debulking surgery 3 cycles postoperative chemotherapy Randomized till date: 404/686

19 TRIAL ON RADICAL UPFRONT SURGERY IN ADVANCED OVARIAN CANCER

20 OVAIO RECIDIVA PLATINO RESISTENTE
Attualmente non protocolli attivi nelle platino resistenti In attivazione In arrivo: MITO 27 Pembro MITO 29 Decitabina

21 OVAIO RECIDIVA PLATINO SENSIBILE
MITO 17 (INT Napoli) Retrospetive trial on tertiary cytoreductive surgery in recurrent ovarian cancer MITO 18 Horse (Policlinico Gemelli Roma) ENGOT –OV 27 (INT Napoli) Farletuzumab in platinum sensitive ovarian cancer with low (<105 u/mL) CA125 (INT Napoli) ICON 9 (Policlinico Gemelli Roma) Coming soon: OREO OVAIO RECIDIVA PLATINO SENSIBILE

22 Tertiary cytoreductive surgery in recurrent epithelial ovarian cancer
17 Published on Gynecologic Oncology on July 2017

23 Tertiary cytoreductive surgery in recurrent epithelial ovarian cancer
Study design Multicenter, retrospective Objectives To evaluate the impact of TCS on survival; To determine predictors of complete TCS; To formulate a hypothesis for selection criteria/predictive factors for successful complete TCS (such hypothesis is intended to form the basis for a subsequently planned prospective trial evaluating a predictive model for complete TCS in recurrent EOC).

24 Tertiary cytoreductive surgery in recurrent epithelial ovarian cancer
Inclusion criteria - Patients with a second relapse of EOC (including tubal and peritoneal epithelial cancers) undergoing elective TCS during the period ; - PS according to ECOG 0 – 1; - TFI ≥6 months after completion of first−/second−line therapy. Exclusion criteria - patients operated on for strictly palliative purposes; - PS according to ECOG >1; - serological recurrence only (CA125 serum levels >35 UI/mL); - non-epithelial or borderline tumors; - TFI <6 months after completion of first−/second−line therapy; - patients with second malignancies who had been treated by laparotomy or who had a therapy that could interfere with the treatment of relapsed ovarian cancer.

25 Tertiary cytoreductive surgery in recurrent epithelial ovarian cancer
An appropriate data-base has been designed and will be available online to participating centers Centralised analysis c/o NCI – Naples Data Center

26 Tertiary cytoreductive surgery in recurrent epithelial ovarian cancer
Participating site status Country Sites Group PI Recruitment Naples, National Cancer Institute MITO Greggi S. Active London, Imperial College AGO/NOGGO Fotopoulou C. Berlin, Charité Medical University Sehouli J. Pending Essen, Kliniken Essen Mitte AGO Du Bouis A. CONTACT INFORMATION: STEFANO GREGGI, MD, PhD

27 Surgery plus Hyperthermic Intra-PEritoneal Chemotherapy (HIPEC) versus surgery alone in patients with platinum-sensitive first recurrence of ovarian cancer: a prospective randomized multicenter trial. PROTOCOL ID: HORSE Hyperthermic intra-peritoneal chemotherapy (HIPEC) in platinum-sensitive Ovarian cancer recurrence: Randomized trial on Survival Evaluation.

28 Inclusion Criteria Exclusion Criteria
years -first recurrence of EOC with measurable or not measurable lesions, but evaluable (upwards of Ca125 for 2 consecutive assessments). -ECOG-performance status ≤ 2 -disease limited to the abdominal cavity with or without extraperitoneal spread considered resectable at intraoperative evaluation -recurrence after ≥6 months from primary treatment -Previous-based chemotherapy of carboplatin and taxanes -Peritoneal Washing-positive in the presence of other abdominal disease surgically resectable -Adequate respiratory, hepatic, cardiac, kidney and bone marrow function -Patient compliant and psychologically able to follow the trial procedures Exclusion Criteria - Non-epithelial ovarian cancer or borderline ovarian tumor - Pregnancy or breastfeeding - Major depressive disorder even in treatment or minor mood disorders - Impairment of bone marrow, respiratory, hepatic or renal function -Cardiac, neurological or metabolic uncontrolled disease - Active infection or other neoplastic disease in progress -Bowel obstruction -No clear-peritoneal disease at surgical exploration - Ascites> 500 ml (the TAC) -Maintenance therapy with Antiangiogenic -Secondary or tertiary recurrence, or previous HIPEC, or previous second or third line chemotherapy. apr. ’19

29 Patients included (inclusion/exclusion criteria)
LPT: Maximal Surgical Effort Patients eligible (CC-0; CC-1) Patients not eligible (CC>1) Randomization CDDP 75 mg/m2 in 2L/m2 SF temperature 41.5C for 60 min 79 HIPEC NO 79 HIPEC YES Pl based CHT Pl based CHT Drop-out FU FU Drop-out apr. ’19

30 Status: Enrolment ended Enrollement 158 patients
79 ARM A 79 ARM B apr. ’19

31 Principal Investigator
Arruolamento per centro CODICE CENTRO ISTITUTO Principal Investigator Pazienti Arruolate Braccio A Braccio B 001 Fondazione Policlinico Universitario Agostino Gemelli IRCCS Giovanni Scambia 122 62 60 003 Casa di cura Fondazione Giovanni Paolo II Campobasso Vito Chiantera 7 2 5 005 A.O. per l'emergenza Cannizzaro SC di Ginecologia ed Ostetricia Paolo Scollo / 006 IEO di Milano Angelo Maggioni 1 007 IRCCS Arcispedale S. Maria Nuova, Oncologia Medica, Martino Abrate 6 3 029 Centro di Chirurgia Oncologica avanzata c/o Clinica Chirurgica Enricomaria Pasqual 030 Istituto Nazionale Tumori Napoli Stefano Greggi 032 Ospedale Sant'Orsola Malpighi -Bologna- Pierandrea De Iaco 15 8 038 IRCCS Centro di Riferimento Oncologico CRO Aviano (PN) Giorgio Giorda 046 AUSLL 11 di Empoli Ospedale San Giuseppe Empoli (FI) PI Marco Filippeschi - SOMMA 158 79 apr. ’19

32 Arruolamento per centro
apr. ’19

33 BGOG-ov18 Randomized Phase II of chemo +/- Farletuzumab
Carbo PLD x6 + Farletuzumab : Concomittant + maintenance till PD loading dose for the first 2 weeks of 10 mg/kg farletuzumab (double blind), followed by 5 mg/kg weekly First recurrent platin sensitive high grade serous ovarian carcinoma CA125 < 3UNL Evaluable or measurable according to RECIST N = 210 Carbo PLD 2:1 Carbo PLD x6 + Placebo : Concomittant + maintenance Investigator Choice 1:1 Carbo Pacli + Farletuzumab : Concomittant + maintenance till PD loading dose for the first 2 weeks of 10 mg/kg farletuzumab (double blind), followed by 5 mg/kg weekly Carbo Pacli 2:1 Carbo Pacli x6 + Placebo : Concomittant + maintenance FPI: Mar 2015 (US); Aug 2015 (EU) Primary endpoint: PFS * (Assumed HR = 0.667, investigator read) Secondary endpoints: OS, Pt free interval, OR, TTR, DR, safety, PK and exposure-response

34 ENGOT-ov27 169/210 patients randomized
REGION COUNTRY DATA SITES ACTIVATED SUBJECT ENROLLMENT # of countries Name Ever opened for Recruitment Screened Randomized Europe 5 Italy 12 46 25 Spain 9 34 Belgium 7 24 14 Germany 11 UK 3 4 North America 1 US 44 121 77 Asia-Pacific Japan 8 26 19 Total 92 267 169

35

36

37 618 patients to enroll

38

39 Inclusion criteria Histologically proven diagnosis of high grade serous or endometrioid carcinoma of the ovary, fallopian tube or peritoneum, progressing more than 6 months after day 1 of the last cycle of first-line platinum-based chemotherapy and requiring treatment with second-line platinum-based chemotherapy. Patients may be included post-surgery for relapsed disease if undertaken more than 6 months after progression from first-line therapy. CT or MRI proven relapsed disease at first recurrence (measurable or non-measurable) prior to starting second-line treatment or surgically debulking. Patients who have CT/MRI non-measurable disease recurrence should be assessed by GCIG CA125 criteria of progression. Completed a minimum of 4 cycles of platinum-based chemotherapy for first relapse (2nd line treatment) with at least a partial response on imaging (CT or MRI) by RECIST v1.1 if measureable disease or CA125 response by GCIG criteria if non-measurable disease. No CT/MRI or CA125 evidence of progression after surgical debulking and chemotherapy (above). Prior front-line maintenance therapy with bevacizumab is permitted

40 6 MITO CENTERS + 5 MANGO CENTERS
Centre Clinician/datamanager Expected no./year 1 Candiolo (TO) Oncologia Medica IRCC Università degli Studi di Torino Giorgio Valabrega/Celeste Cagnazzo 6 2 Roma Ginecologia Oncologica Policlinico A Gemelli Giovanni Scambia, Vanda Salutari/Michela Panella 10 3 Napoli Oncologia Medica Istituto Nazionale Tumori Fondazione G. Pascale Sandro Pignata/Jane Brice 8-10 4 Milano Ginecologia Istituto Nazionale Tumori Domenica Lorusso/Iolanda Pulice 5 Brindisi Oncologia Medica A.O. “A. Perrino” di Brindisi Saverio Cinieri/Pasqualinda Ferrara 5-8 Bologna Oncologia Ospedale S.Orsola Malpighi Università di Bologna Claudio Zamagni TOTAL 44-52 First Patient in UK In June With regards to the Italian level: Research Agreement currently drafting

41 OVAIO TUMORI RARI MITO 14 (Dott Breda): chiuso, manoscritto in preparazione MITO 22 (Policlinico Gemelli Roma) piccole cellule, chiuso, elaborazione dati in corso MITO 19 (INT Napoli): Studio retrospettivo sui tumori sierosi di basso grado MITO 21 (Dr Artioli) : Studio retrospettivo tumori BRCA mutati Studio Alienor (INT-Milano; ENGOT, chiuso) MITO SARC 1 (Dr Ferrandina) Studio retrospettivio sarcomi uterini

42 MITO 14 AGGIORNAMENTO Dott. Enrico Breda

43 MANUSCRIPT IN PREPARATION
Ospedale N° Fatebenefratelli Tiberina (RM) 45 Dipartimento Oncologia Ospedale Mirano (VE) 15 Università Bari Policlinico II (BA) 62 Santa Maria della Misericordia (PG) 8 San Raffaele (MI) 68 Centro Riferimento Oncologico Aviano (UD) 35 Istituto Tumori (MI) 47 Policlinico Gemelli (RM) 201 Azienda Ospedaliera Univ Integrata (VR) 51 Istituto Nazionale Tumori (NA) 67 Campus Biomedico (RM) 18 Mater Salutis ULSS21 Legnago (VR) 20 II Università Napoli (NA) IRCCS Casa sollievo della sofferenza (FG) 13 Ospedale Guastalla (RE) 5 Ospedale Santa Maria Goretti (LT) 27 Ospedali Riuniti (BG) 92 Ospedale di Trento (TN) 39 Ospedale Canizzaro (CT) 40 Ospedale Civile (CZ) 19 Policlinico S. Orsola (BO) 152 INT Regina Elena (RM) Cattedra Oncologica Medica Federico II (NA) 24 III Clinica di Ginecologia e Ostretricia (BA) 1 Arcispedale Santa Maria Nuova (RE) Ospedale S. Giuseppe USL 11 Toscana Ospedale Faenza 6 Vici INT Regina Elena B (RM) Ospedale Civile Boldrini Thiene (VI) 34 SCDU Ginecologia e Ostetricia Ospedale Mauriziano (TO) 81 Università La Sapienza (RM) 44 1359 MANUSCRIPT IN PREPARATION

44 Mito 22: obiettivi endpoint primari endpoint secondari
Rischio di recidiva in pazienti operate RR a CHT, OT e terapia combinata in I linea e in linee successive endpoint secondari PFS, OS Profilo di tossicità KRAS, BRAF, p53 correlazione tra mutazione di BRAF e outcome favorevole??? Grisham, BRAF mutation is associated with early stage disease and improved outcome in patients with low-grade serous ovarian cancer, Cancer 2013; 1;119(3): Wong, BRAF mutation is rare in advanced-stage low-grade ovarian serous carcinomas, Am J Pathol, 2010; 177(4):1611-7

45 Mito 22 criteri di inclusione LGSOC/Recidiva Invasiva di SBLT operato
Diagnosi posta tra e il Preparato istologico per revisione centralizzata Età > 18 aa EMENDARE?? …SI POTREBBE SPOSTARE IL TERMINE DELLA DATA DIAGNOSI ALL’ INT Napoli Ist Regina Elena CRO Aviano Pol Univ A. Gemelli Roma

46 Informazioni operative (1)
ATTESA DATI UMBERTO I e GEMELLI per raggiungere target

47 Results Coming Soon NEXT MITO MEETING
Studio osservazionale sul trattamento dei tumori a piccole cellule dell’apparato genitale femminile Results Coming Soon NEXT MITO MEETING

48 MITO 21  Studio Retrospettivo Multicentrico: Correlazione tra genotipo, fenotipo e outcome clinico nei tumori ovarici ereditari BRCA1 e BRCA2 mutati Centro Coordinatore Oncologia Mirano VE ULSS13- Grazia Artioli

49 Tipologia dello studio
Studio retrospettivo multicentrico Tipologia dello studio Pz afferenti ai centri MITO affetti da EOC (ca epiteliale ovarico, ca tubarico, ca primitivo del peritoneo) e portatrici di mutazione germinale a carico dei geni BRCA 1 e/o BRCA 2, con test genetico eseguito tra il 1995 e 2017 Popolazione oggetto dello studio Le mutazioni germinali di BRCA1 e BRCA2 potrebbero contribuire a determinare sia la risposta al trattamento del carcinoma ovarico sia la sua aggressività biologica Razionale dello studio Raccolta dati attraverso un database Disegno dello studio Valutare la correlazione tra i singoli tipi di mutazione germinale a carico di BRCA1 e BRCA2 e le caratteristiche clinico-patologiche e l’outcome al trattamento nelle pazienti affette da EOC Obiettivi dello studio Approvazione CE Centro Coordinatore: Approvazione 1° emendamento: Prolungamento del tempo di osservazione (fino al 2016) Aggiunta della causa di morte (EOC vs ca mammella) Aggiunta delle informazioni su uso di PARPi Chiusura arruolamento Dicembre 2017 Analisi in corso Tempi dello studio

50 XXXI Riunione Nazionale MITO
MITO 21 RISULTATI   15 centri MITO PARTECIPANTI 342 casi ARRUOLATI 15/04/2019 XXXI Riunione Nazionale MITO

51 XXXI Riunione Nazionale MITO
MITO 21 RISULTATI Abstract accettato come POSTER DOES BREAST CANCER AFFECT PROGNOSIS IN A BRCA-MUTATED OVARIAN CANCER COHORT? THE MITO 21 STUDY - A SUBGROUP ANALYSIS Authors: Borgato Lucia, Arcangela De Nicolo, Domenica Lorusso, Sandro Pignata, Gennaro Cormio, Simona Scalone, Maria Ornella Nicoletto, Giorgio Valabrega, Filippo Greco, Emanuela Rossi, Ilaria Spagnoletti, Ugo De Giorgi, Michele Orditura, Anna Maria Mosconi, Anila Kardhashi, Stefano Bogliolo, Simone Mocellin, Grazia Artioli XXXI Riunione Nazionale MITO

52 … primi risultati dell’analisi sui doppi tumori
265 pts 77 pts XXXI Riunione Nazionale MITO

53 Età di insorgenza della 1° neoplasia
… primi risultati dell’analisi sui doppi tumori Characteristics BRCA1 n BRCA2 TOTAL DPBOC 40 20 60 Breast cancer as 1st tumor 31 16 47 Ovarian cancer as 1st tumor 9 4 13 Age at diagnosis of 1st tumor, media if Breast Cancer if Ovarian Cancer 47 (32-81) years 54 (43-67)years Caratteristiche delle pz Tipo di mutazione correlata al gene e all’insorgenza della neoplasia Mutazione BRCA1 c.5266dupC 9 casi descritti frameshift variant Età di insorgenza della 1° neoplasia 15/04/2019 XXXI Riunione Nazionale MITO

54 XXXI Riunione Nazionale MITO
conclusioni Abbiamo definito le caratteristiche cliniche e genetiche di un’ampia casistica italiana di donne affette da BOC e mutazione BRCA1 / BRCA2 La finalità dello studio MITO21 è valutare eventuali associazioni genotipo/fenotipo in una coorte di donne BRCA mutata, in questa analisi di sottogruppo abbiamo indentificato una associazione statisticamente significativa tra variante patogenetica PS ed insorgenza di neoplasia mammaria come prima neoplasia. Prossima tappa: abstract a Paper 20-21 Giugno XXXI Riunione Nazionale MITO

55 Avastin and weekly pacLItaxel use in sEx cord-stromal ovariaN tumORs
ALIENOR ENGOT- OV7 Avastin and weekly pacLItaxel use in sEx cord-stromal ovariaN tumORs A randomized, open label, phase II trial of bevacizumab plus weekly paclitaxel followed by maintenance with bevacizumab monotherapy versus weekly paclitaxel followed by observation in patients with relapsed ovarian sex-cord stromal tumors

56 Standard surveillance
STUDY DESIGN Bevacizumab 15mg/Kg every 3 weeks Paclitaxel alone 80mg/m², IV, at D1, D8 and D15 every 4 weeks Paclitaxel 80mg/m², IV, D1, D8 and D15 every 4 weeks + 10mg/kg, IV, D1 and D15 RANDOMISATION Maximum of 6 cycles Up to 1 year or until PD / intolerance Arm A Arm B Standard surveillance Standard of care PD or Toxicity At the investigator discretion Population : Patients with an histologically confirmed diagnosis of ovarian sex-cord stromal tumor in relapse after a platinum-based chemotherapy. Stratification Anterior chemotherapy lines : 1 or 2 vs 3 and more Platinum Free Interval Interval (PFI) <12 months vs >12 months Primary objective : Clinical benefit rate (non-progression rate after 6 months of treatment) GCIG Meeting-Melbourne 2014

57 ALIENOR STUDY Enrollment period : 36 months First Patient In : February 2013 Treatment + maintenance : 18 months Last Patient Out of Maintenance : August 2017 Follow-up : 36 months Last Patient Out : August 2020

58 Enrollment closed on

59 ITALIAN SITES AIFA approved on 01.12.2015
Principal Investigator Patient enrolled Istituto Nazionale Tumori – Milano – Coordinating center Domenica Lorusso 4 patients Istituto Tumori Pascale - Napoli Sandro Pignata 3 patients Ospedale San Raffaele - Milano Giorgia Mangili 1 patient IRST di Meldola Ugo De Giorgi - ORAL PRESENTATION ESMO 2018!

60 MITO 21 Centro Coordinatore : Oncologia - Mirano VE
Studio Retrospettivo Multicentrico: Correlazione tra Genotipo, Fenotipo e Outcome Clinico nei Tumori Ovarici Ereditari BRCA1 e BRCA2 mutati Centro Coordinatore : Oncologia - Mirano VE Grazia Artioli e Lucia Borgato

61 15 CENTRI PARTECIPANTI PZ ATTESE: 300 PZ ARRUOLATE: 338 CENTRO MITO
Referente Pz arruolate (n) 1. Centro Coordinatore OncoEmatologia MIRANO (VE) Artioli G, Borgato L 25 2. Istituto Nazionale Tumori - MILANO Lorusso D 86 3. Istituto Nazionale Tumori - NAPOLI Pignata S 54 4. Università di Bari - BARI Cormio G 32 5. Centro di Riferimento Oncologico - AVIANO Scalone, Sorio R 28 6. IRCCS IOV - PADOVA Nicoletto MO 23 7 IRCCS - CANDIOLO (TO) Valabrega 8. Oncologia – LEGNAGO (VR) Greco F 14 9. IRCCS Osp. Oncologico (BARI) Kardhashi 8 10. Oncologia Medica (AVELLINO) Gridelli C, Rossi E 11 11. IRST Meldola U. De Giorgi 7 12. Oncologia- FBF Roma I.Spagnoletti 6 13. Oncologia ,Osp. Napoli M.Orditura 5 14. Oncologia, Osp Santa Maria della Misericordia , Perugia Mosconi 15. Oncologia , Osp S. Matteo – Pavia S.Bogliolo 3 TOTALE 338 PZ ATTESE: 300 PZ ARRUOLATE: 338

62 ARRUOLAMENTO chiuso: termine dello studio Dicembre 2017
ANALISI IN CORSO PUBBLICAZIONI: presentazione poster ESGO 2017 Per il 2018 Abstract ESMO 2018 Scrivere paper sui doppi tumori Breast and ovarian cancer

63

64 MITO SARC -1 STUDIO OSSERVAZIONALE RETROSPETTIVO SU ANDAMENTO CLINICO E TRATTAMENTO NELLE PAZIENTI AFFETTE DA SARCOMA UTERINO

65 Criteri di inclusione/esclusione
Diagnosi di sarcoma uterino (LMS, ESS, USS, Adenosarcoma, Pecoma) OPPURE di recidiva di sarcoma uterino (LMS, ESS, USS, Adenosarcoma, Pecoma) negli anni in studio Età > 18 aa Consenso alla raccolta dati Criteri di esclusione Diagnosi diversa da sarcoma uterino (LMS, ESS, USS, Adenosarcoma, Pecoma)

66 ANALISI STATISTICA

67 CARCINOMA DELL’ENDOMETRIO
Trattamento conservativo : ECCO study (INT Napoli) Linfonodo sentinella nel carcinoma dell’endometrio (INT Milano) ENGOT EN2-EORTC (Mauriziano-Torino/ INT Napoli) A phase II trial of postoperative chemotherapy or no further treatment for patients with node negative stage I-II intermediate or high risk endometrial cancer. PALEO study (Policlinico Gemelli Roma): A randomized phase II trial of Palbociclib in combination with letrozole versus letrozole for patients with oestrogen receptor positive recurrent endometrial cancer. In attivazione: SIENDO STUDY (Coordinato Candiolo Torino): Coming Soon MITO END 3 (INT-Napoli): Studio randomizzato di fase 2 con Avelumab in combinazione a Carboplatino-paclitaxel vs Carboplatino-Paclitaxel nel carcinoma metastatico/avanzato

68 Endometrial Cancer Conservative treatment
E.C.Co. Endometrial Cancer Conservative treatment A multicentre archive Data collection is made by appropriate eCRFs via the Clinical Trials Unit of National Cancer Institute of Naples (Study Data Center) website

69 Endometrial Cancer Conservative treatment
E.C.Co. Endometrial Cancer Conservative treatment A multicentre archive Project Type / Design & Time Perspective Observational / Patient archive, Prospective (a first phase of three years is planned, eventually followed by further three years) Inclusion Criteria - Conservatively treated endometrial cancer - Informed consent to personal data processing - Existence of an IRB-approved local protocol that allows conservative treatment to be performed (or statement that such treatment is considered as a standard) Interventions & Outcome Measures Data collection - Primary Outcome Measures: proportion of complete regression, duration of response, frequency and pattern of relapse, frequency of metachronous ovarian cancer, tumor-related deaths; Secondary Outcome Measures: treatment related morbidity, frequency of spontaneous pregnancies, frequency of pregnancies after ART, pattern of residual disease on definitive surgical specimens Treatment Since this is a archive, treatment is not dictated by a protocol, however, treatment has to be administered according to a IRB-approved local protocol (except for the countries where conservative treatment can be given outside a IRB-approved study because considered as a standard procedure)

70 Endometrial Cancer Conservative treatment
E.C.Co. Endometrial Cancer Conservative treatment A multicentre archive A new CRF has been added Mutational Status

71 Endometrial Cancer Conservative treatment A multicentre archive
E.C.Co. Endometrial Cancer Conservative treatment A multicentre archive Participation ( ) Country Sites PI #pts registered Naples, NCI Greggi S. 33 Rome, Catholic University Scambia G 18 Wien, University Polterauer S. 7 Bergamo, ‘Papa Giovanni XXIII’ H Malandrino C. 6 Naples, Ist University Zullo F. 3 Milan, ‘S. Raffaele’ H De Marzi P. 4 Bari, ‘Giovanni Paolo II’ H Cormio G. 1 Fudan, University Chen X. - Leiden, University Rome, NCI Vizza E. Parkville, Royal Women's H Tot. 72

72 160 Pazienti con ca endometrio tipo I-II early, stadio FIGO I-II
PROTOCOLLO Iniezione isteroscopica vs. cervicale di tracciante per identificazione del linfonodo sentinella nel tumore dell’endometrio: studio randomizzato, multicentrico P I Dr Antonino Ditto, M.D. 160 Pazienti con ca endometrio tipo I-II early, stadio FIGO I-II Work-up and Lps : assenza di diffusione peritoneale e/o linfonodi bulky RANDOMIZZAZIONE 1-1 Inoculo cervicale N= 80 Identificazione ed asportazione linfonodi sentinella pelvici e/o para-aortici Ultrastaging Inoculo endometriale N=80 La linfoadenectomia sistematica è lasciata alla discrezione del chirurgo

73 Status centri CENTRO PI Status
Milano - INT Dr. Antonino Ditto Attivo dal Bologna Dr.ssa Perrone Attivo dal Varese Prof. Fabio Ghezzi Attivo dal Firenze Dr. Giuseppe Cariti In attesa della lettera contratto Roma Prof. Enrico Vizza In attesa della lettera contratto Aviano Dr. Giorgio Giorda In attesa di Approvazione Etica Bari - Policlinico Prof. Ettore Cicinelli In attesa di Approvazione Etica Bari - IRCCS “ Giovanni Paolo II” Prof. Gennaro Cormio In attesa di Approvazione Etica Catania Prof. Paolo Scollo Approvazione CE

74

75 Randomized till date = 192/240
Postoperative chemotherapy or no further treatment for patients with node-negative stage I-II intermediate or high risk endometrial cancer ENGOT-EN2-DGCG NCT N=240 1:1 randomization Chemotherapy Carboplatin-Paclitaxel x 6 + Brachytherapy Endometrioid: Stage I - G3; II Non-endometrioid: Stage I-II Supported by Observation + Brachytherapy Randomized till date = 192/240

76 Key Inclusion Criteria:
Postoperative chemotherapy or no further treatment for patients with node-negative stage I-II intermediate or high risk endometrial cancer ENGOT-EN2-DGCG NCT Key Inclusion Criteria: Only node-negative patients are eligible Endometrial carcinoma with one of the following postoperative FIGO 2009 stage and grade: Stage I grade 3 endometrioid adenocarcinoma Stage II endometrioid adenocarcinoma Stage I and II type 2 histology (clear cell, serous, squamous cell carcinoma, or undifferentiated carcinoma) Hysterectomy; bilateral salpingo-oophorectomy; pelvic lymphadenectomy: min 12 pelvic nodes (6 from each side). Para-aortic LNE is optional Adjuvant vaginal brachytherapy is permitted in both arms WHO performance status of 0-2 Key Exclusion Criteria: External Beam Radiotherapy Concurrent cancer therapy Concurrent treatment with an anticancer investigational agent or participation in another anticancer clinical trial Previous or concurrent malignant disease except for curatively treated carcinoma in situ of the cervix or basal cell carcinoma of the skin

77 Postoperative chemotherapy or no further treatment for patients with node-negative stage I-II intermediate or high risk endometrial cancer ENGOT-EN2-DGCG NCT INSTITUTIONS PI RANDOMIZED PATIENTS Istituto Nazionale Tumori “G. Pascale”, Naples AUTORIZZATO Stefano Greggi 7 Istituto Nazionale Tumori, Milano Domenica Lorusso Istituto Nazionale Tumori “Regina Elena”, Roma NON AUTORIZZATO Enrico Vizza  - Università Cattolica del Sacro Cuore, Roma Giovanni Scambia Università di Bologna, Bologna Pierandrea De Iaco Università di Bari, Bari Gennaro Cormio Ospedale di Faenza (Ravenna) Stefano Tamberi Ist. Scientifico Romagnolo per lo Studio e la Cura dei Tumori Meldola (Forlí) NON AUTORIZZATO Ugo De Giorgi Centro di  Riferimento Oncologico, Aviano Giorgio Giorda

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80 CENTRI MITO Submitted to AIFA, Research Agreement currently drafting.
Centre 1 Candiolo (TO) Oncologia Medica IRCC Università degli Studi di Torino Giorgio Valabrega/Celeste Cagnazzo 2 Roma Ginecologia Oncologica Policlinico A Gemelli Giovanni Scambia, Vanda Salutari/Michela Panella 3 Napoli Oncologia Medica Istituto Nazionale Tumori Fondazione G. Pascale Sandro Pignata/Jane Brice 4 Milano Ginecologia Istituto Nazionale Tumori Domenica Lorusso/Iolanda Pulice 5 Lecce Oncologia Medica Ospedale “Vito Fazzi” Graziana Ronzino 6 Bologna Oncologia Ospedale S.Orsola Malpighi Università di Bologna Claudio Zamagni 7 Meldola Oncologia Medica I.R.S.T  Ugo De Giorgi Submitted to AIFA, Research Agreement currently drafting. Problemi per la registrazione del gruppo NSGO nella piattaforma AIFA

81 CARCINOMA DELLA CERVICE UTERINA
BGOG-CX1 (INT Napoli) Nintedanib in cervical cancer In attivazione: - Studio Abrax (INT Milano) Linfonodo sentinella nella cervice uterina

82 Coordinating investigator: Prof Dr. Ignace Vergote
BGOG-cx1 Randomized double-blind Phase II study comparing carboplatin + paclitaxel with or without concomitant and maintenance Nintedanib in advanced or recurrent cervical carcinoma ENGOT model A Sponsor: BGOG Coordinating investigator: Prof Dr. Ignace Vergote

83 BGOG-cx1: study design primary endpoint PFS
Patients (N= 120) with advanced stage (FIGO stage IVB) OR recurrent carcinoma of the cervix 1:1 Randomization IXRS Nintedanib* 200 mg p.o. BID PLUS Paclitaxel 175 mg/m2 + carboplatin AUC5 Every 21 days for 6 cycles Nintedanib monotherapy up to 120 weeks Placebo* p.o. BID Placebo monotherapy up to 120 weeks Stratification 1. Primary advanced Stage IVB versus recurrent disease. 2. If recurrent, prior line of chemotherapy for metastatic disease or not * Nintedanib/placebo to be omitted on the day of iv. chemotherapy

84 Timelines BGOG-cx1: study update Milestone Estimated timing
First patient in March 2014 Last patient in August 2018 Last patient out August 2020 Primary analysis 1,5 y after LPI (March 2020) Secondary analysis 5 y after LPI (August 2023) Total Enrollment (by May 2018) 110/120 pts

85 BGOG-cx1: study update Site activations Italy Site Group
Expected Accrual Activation Accrual 39001 MITO Istituto Nazionale Tumori-Pascale Napoli - Dr. Pignata 3-6 2/2/2017 1 39002 National Cancer Institute Milano – Dr. Lorusso 8-10 16/5/2017 9 39003 Centro Riferimento Oncologico – Dr. Sorio EXPECTED 01/2018 39004 Policlinico A Gemelli – Dr. Scambia 4-8 14/05/2018 39005 Azienda Ospedaliera Cannizzaro – Dr. Scollo 29/03/2018 39006 MaNGO Reggio Emilia – Dr. Bologna 4 ESITO NEGATIVO 39007 Pisa – University – Dr. Gadducci NOT EVALUATED 39008 Padova Istituto Oncologico Veneto – Dr. Nicoletto 9/01/2018 39009 Torino – S. Anna, Dr. Zola 2/5/2017 39010 Torino – Mauriziano, Dr. Ferrero 9/5/2017 5 39011 Brescia - Spedali Civili-Università di Brescia, Dr. Tognon TOTAL : 11 centers +/- 40 patients 21 patients

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